HIV a global health problem

1. PHARMACOTHERAPY OF HIV
MANAGEMENT
Dr. Sourav Chakrabarty
Post-graduate trainee
Department of Pharmacology

2. Overview
• Introduction
• HIV virus
• Pathophysiology of AIDS
• Anti-retroviral drugs
• Principles of anti-HIV chemotherapy
• WHO 2013 guideline
• Conclusion

3. Introduction
• HIV/ AIDS- a global threat to mankind
• 33 millions of HIV infected worldwide
• Cripples immune system, affects CNS, Kidney, vascular
system, mucosa.
• Still no cure,
• No vaccine

4. HIV virus

5. Life cycle of HIV virus

6. History of natural disease

7. Acquired Immune Deficiency Syndrome
• Two parameters:
1. Clinical conditions
2. CD4+ T lymphocyte count at blood
• AIDS- if one or more specific opportunistic illness has been
diagnosed OR CD4 T+ Lymphocyte <200/µl

8. Conditions defining AIDS

9. Anti-retroviral drugs- sites of action

10. History of anti-retroviral drugs
• Zidovudine – synthesized in 1964
Anti-HIV activity- 1985
• Saquinavir – 1995
• NNRTI- 1998
• Raltegravir- 2007

11. Anti-retroviral drugs
Nucleoside Reverse
Transcriptase
Inhibitors(NRTI)
Zidovudine (AZT) Stavudine (d4T) Tenofovir disoproxil
(TDF)
Lamivudine(
3TC)
Didanosine (ddl) Zalcitabine(DDC) Emtricitabine (FTC) Abacavir
(ABC)
Non-nucleoside
Reverse Transcriptase
Inhibitors(NNRTI)
Nevirapine(NVP) Delavirdine (DLV) Efavirenz (EFV) Etravirine
(ETV)

12. Contd………
Protease
Inhibitors
Saquinavir (SQV) Ritonavir (RTV) Amprenavir (APV) Atazanavir(ATV)
Indinavir (IDV) Nelfinavir (NFV) Lopinavir (LPV/r) Fosamprenavir
(FPV)
Tipranavir (TPV) Darunavir
(DRV)
Entry Inhibitors Enfuvirtide (T-20) Maraviroc
(MVC)
Integrase
Inhibitor
Raltegravir (RAL)

13. Nucleoside/ Nucleotide Reverse
Transcriptase Inhibitors(NRTI)

14. Intracellular activation of NRTIs

16. Zidovudine
• Active against HIV 1 & 2, HTLV 1 & 2.
• more active in lymphocytes than in monocyte-macrophage cells
• Dose- 300 mg twice a day
• Crosses placenta & BBB.
• Untoward Effects-
1. fatigue, malaise, myalgia, nausea, anorexia, headache and
insomnia.
2. Bone marrow suppression
3. nail hyperpigmentation, myopathy
4. Serious hepatic toxicity

17. Lamivudine
• First line NRTI
• manufactured as the pure 2Rcis(−)enantiomer
• More active in resting cells
• Dose- 300 mg once daily
• Untoward Effects- Neutropenia, headache, and nausea
• caution in using in co-infection with HBV

18. Tenofovir
• only nucleotide analog
• Available only as the disoproxil prodrug
• Incomplete ribose ring
• Dose- 300mg OD
• Untoward Effects-well tolerated, rarely acute renal
failure and Fanconi’s syndrome
• Drug interaction with Didanosine

19. Emtricitabine
• chemically related to lamivudine
• one of the least toxic anti-retroviral drugs
Abacavir
• Dose: 600 mg once daily
• eliminated by metabolism by alcohol dehydrogenase, and
by glucuronidation
• fatal hypersensitivity syndrome(HLA-B*5701 genotype)

20. Didanosine
• Dose-200 mg twice daily
• Acid labile, hence needs antacid buffer
• Not well tolerated
• peripheral neuropathy and pancreatitis

21. Non-Nucleoside Reverse Transcriptase
Inhibitors(NNRTI)
• Active against HIV 1 only
• No activity against host cell DNA polymerases.
• 4 agents- Nevirapine/Efavirenz/ Delavirdine/ Etravirine.
• Susceptible to high-level drug resistance
• Cross-resistance

22. Mechanism of action

23. Pharmacokinetics

24. Efavirenz
• First line NNRTI
• Once daily dosing
• Highly teratogenic
• Adverse effect- CNS toxicities
• Rash

25. Nevirapine
• First line ART both for active treatment and for PPTCT
• Induces own metabolism
• Untoward Effects- Rash, increased liver enzymes
• Severe & fatal hepatitis in pregnancy.
• PPTCT- A single oral intrapartum dose of 200 mg nevirapine
followed by a single dose given to the newborn

26. HIV Protease Inhibitors
• Inhibit virus aspartyl protease
• Highly variable pharmacokinetics
• Metabolised by CYP 3A4
• Potential for metabolic drug interactions
• ADR-nausea, vomiting, and diarrhea

27. Mechanism of action
The viral
maturation is
inhibited
The production
of the viral
particle is
inhibited
Act as protease
inhibitor in which
block the action
of protease

28. Pharmacokinetics

29. Saquinavir
• First approved Protease inhibitor
• Poor oral bioavailability
• Dose- 600 mg TDS
Lopinavir
• Active against both HIV-1 and HIV-2
• Extensive metabolism by CYP 3A4
• lopinavir/ritonavir co-formulation in a fixed 4:1 ratio
• ADRs- loose stools, diarrhea, nausea, and vomiting

30. Ritonavir
• Mostly used as a pharmacokinetic enhancer (CYP 3A4
inhibitor)
• Dose-
antiretroviral treatment 600 mg twice daily
Booster dose-100/ 200 mg once or twice daily
• ADRs- GI upset, lipodystrophy

31. Entry Inhibitors
• Two drugs- Enfuvirtide and Maraviroc
• gp 41 and CD4 interactions- enfuvirtide
• gp 120 and CCR5 interactions- maraviroc

32. Maraviroc

33. Contd……..
• Active only against CCR5-tropic strains of HIV
• Three different starting dose-
1. with most CYP3A inhibitors- 150mg BD
2. with most CYP3A inducers- 600mg BD
3. With other- 300mg BD
• generally well tolerated

34. Enfuvirtide
• only approved parenteral antiretroviral drug
• Evolved first as vaccine
• High cost to manufacture
• ADRs- injection-site reactions,
lymphadenopathy , pneumonia
• Indication- only in treatment-experienced adults

35. Enfuvertide bind to gp 41 & prevent
change in shape require for membrane
fusion & viral entry into target cell.
gp41 undergoes change in shape
facilitating fusion of viral membrane with
cell
gp120 must bind to host CD4+ cell
Entry of HIV-1 into host cell by fusion
virus & cell membrane
Mechanism of action

36. Integrase Inhibitors

37. GUIDELINES FOR
HIGHLY ACTIVE
ANTIRETROVIRAL THERAPY
(HAART):
HOW TO USE THE DRUGS?
Based on:
Rapid Advice: antiretroviral therapy for HIV infection in adults and adolescent
Guidelines For The Management Of Adult HIV Infection With Antiretroviral Therapy
http://www.who.int/hiv/pub/arv/rapid_advice_art.pdf

38. HAART
Highly active antiretroviral therapy (ART) using 3 or more active
anti HIV drugs from at least 2 different class with the aim of
achieving durable viral suppression to undetectable levels, the
therapeutic goal under most clinical circumstances.

39. BEFORE STARTING THE REGIMEN
• Past treatment history
 Any resistance to medications
 Current CD4 and viral load counts
 Compliance to medication
 Pregnancy/lactation
 Concurrent illness (TB/HBV)
• HIV tropism assay

40. GUIDELINES TO START ART
• Start ART in all individuals with a CD4 < 500/µl
• Priority to severe or advanced HIV disease and CD4 < 350/µl
• ART at any CD4 count in PLHIV
 Active TB disease
 HBV co-infection with severe chronic liver disease
 HIV nephropathy
 HIV-positive partners in sero-discordant couples
 Pregnant and breastfeeding women
 Children younger than five years of age
 Stage 3 or later in WHO clinical staging

41. First-line ART
Preferred
first-line regimens
Alternative
first-line Regimens
Adults
(including pregnant and
breastfeeding women and
adults with TB and HBV
coinfection)
TDF + 3TC (or FTC) + EFV
AZT + 3TC + EFV
AZT + 3TC + NVP
TDF + 3TC (or FTC) + NVP
Adolescents
(10 to 19 years) ≥35 kg
AZT + 3TC + EFV
AZT + 3TC + NVP
TDF + 3TC (or FTC) + NVP
ABC + 3TC + EFV (or NVP)
Children 3 - 10 years and
adolescents <35 kg
ABC + 3TC + EFV
ABC + 3TC + NVP
AZT + 3TC + EFV
AZT + 3TC + NVP
TDF + 3TC (or FTC) + EFV
TDF + 3TC (or FTC) + NVP
Children <3 years
ABC or
AZT + 3TC + LPV/r
ABC + 3TC + NVP
AZT + 3TC + NVP

42. • People receiving NVP discontinue because of adverse events
• With EFV no increased risk of birth defects compared with other
ARV drugs during the first trimester of pregnancy
• TDF/FTC or TDF/3TC are the preferred NRTI backbone for
HIV + HBV
HIV with TB and
pregnant women.
• EFV is the preferred NNRTI for
HIV & TB (pharmacological compatibility with TB drugs)
HIV +HBV coinfection (less risk of hepatic toxicity) and
Pregnant women, including first trimester.

43. ART for PMTCT

44. Simplified Infant Prophylaxis doses
Drug Infant age Daily dosing
NVP
Birth to 6 weeks
• Birthweight 2000−2499 g
• Birthweight ≥2500 g
10 mg once daily
15 mg once daily
> 6 weeks to 6 months 20 mg once daily
> 6 months to 9 months
30 mg once daily
> 9 months until breastfeeding ends
40 mg once daily
AZT
Birth to 6 weeks
• Birthweight 2000−2499 g
• Birthweight ≥2500 g
10 mg twice daily
15 mg twice daily
If toxicity from NVP requires discontinuation or if NVP is not available,
infant 3TC can be substituted.

45. Timing of ART with TB
• ART should be started in all TB patients, including drug-resistant
TB, irrespective of the CD4 count
• ATD should be initiated first, followed by ART as soon as possible
within the first 8 weeks of treatment.
• HIV-positive TB patients with profound immunosuppression (CD4
<50) should receive ART immediately within the first 2 weeks of
ATD .
.
• Preferred NNRTI is EFV in patients starting ART while on ATD .

46. ART FOR HIV/HBV CO-INFECTION
• Start ART in all HIV/HBV co-infected individuals who require
treatment for their HBV infection, irrespective of CD4 cell count
or WHO clinical stage
• Start tenofovir and lamivudine or emtricitabine (2 NRTIs =
BACKBONE) containing antiretroviral regimens in all HIV/HbV
co-infected individuals needing treatment

47. HIV-2 infection
• HIV-2 is naturally resistant to NNRTIs
• Treatment-naive people coinfected with HIV-1 and HIV-2 should
be treated with three NRTIs TDF + 3TC / FTC + AZT or AZT +
3TC + ABC or a ritonavir-boosted PI plus two NRTIs.
• In PI-based regimen, the preferred option is LPV/r
• SQV/r and DRV/r are alternative boosted-PI options, but they are
not available as heat-stable fixed-dose combinations.

48. WHO definitions of Treatment failure
Failure Definition Comments
Clinical
failure
Adults and adolescents
New or recurrent clinical event indicating
severe immunodeficiency (WHO clinical
stage 4 condition) after 6 months of
effective treatment
--------------------------------------------------
Children
New or recurrent clinical event indicating
advanced or severe immunodeficiency
(WHO clinical stage 3 and 4 clinical
condition with exception of TB) after 6
months of effective treatment
differentiate from IRIS
For adults, certain WHO
clinical stage 3 conditions
(PTB and severe bacterial
infections) also indicate
treatment failure

49. Immunological
failure
Adults and adolescents
CD4 count falls to baseline (or
below) or Persistent CD4 <100
------------------------------------------
Children < 5 years
Persistent CD4 <200 or <10%
>5 years
Persistent CD4 <100
Without concomitant
or recent infection to
cause a transient fall
in CD4
Virological
failure
Plasma viral load >1000 based
on two consecutive viral load
measurements after 3 months,
with
adherence support
Must be on ART
for at least 6
months before
declaring failure

50. Preferred second-line ART regimens
for adults and adolescents
Target
population
Preferred second-line regimen
Adults and
adolescents
(≥10 years)
If d4T or AZT was used in first-
line ART
TDF + 3TC (or FTC) + ATV/r or LPV/r
If TDF was used in first line
ART
AZT + 3TC + ATV/r or LPV/r
Pregnant
women
Same regimens recommended for adults and adolescents
HIV and TB
Coinfection
If rifabutin is available Standard PI-containing regimens
If rifabutin is not available
Same NRTI plus double-dose LPV/r
(ie, LPV/r 800 mg/200 mg ) or standard
LPV dose with an adjusted dose of RTV
(i.e, LPV/r 400 mg/400 mg )
HIV +HBV
coinfection
AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r)

51. Third-line regimens
• National programs should develop policies for third-line therapy that consider
funding, sustainability and the provision of equitable access to ART
• Third-line regimens should include new drugs likely to have anti HIV activity
such as integrase inhibitors (eg. Raltegravir) and second generation NNRTIs
(eg. Etravirine) and PIs (eg. Darunavir)
• Patients on a failing second-line regimen with no new antiretroviral options,
should continue with a tolerated regimen

52. 52
• All NRTIs**
–Lactic acidosis/fatty liver*
–Lipoatrophy (loss of
subcutaneous fat)
• Anemia
– Zidovudine (AZT, ZDV)
• Pancreatitis*
– didanosine (ddI)
• Neuropathy
– didanosine (ddI)
– stavudine (d4T)
*Potentially life-threatening
**d4T > ddI, AZT > ABC, TDF, 3TC
Serious Adverse Effects of NRTIs

53. 53
Serious Adverse Effects of NNRTIs
• All NNRTIs
–Hepatitis*
–Skin rash
• CNS symptoms
– efavirenz
• Stevens-Johnson syndrome*
– nevirapine
*Potentially life-threatening

54. 54
Serious Adverse Effects of PIs
• All PIs
– Insulin resistance  hyperglycemia and diabetes
– Elevated serum lipids
– Abnormal fat accumulation
– Liver toxicity*
*Potentially life-threatening

55. Conclusion
• HIV replication is controllable
• ART is always lifelong
• Minimum 3 drugs
• Best combination- NRTI+ NRTI+ NNRTI
• NNRTI + PI- Should not be given
• But above all, Prevention from HIV is the best way

56. VACCINE???
IS THERE ANY VACCINE AVAILABLE??
IS IT POSSIBLE TO MANUFACTURE ONE??

57. THANK YOU